Slusher et al.

Trials 2013, 14:446

http://www.trialsjournal.com/content/14/1/446
TRIALS

STUDY PROTOCOL Open

Access

Treatment of neonatal jaundice with filtered

sunlight in Nigerian neonates: study protocol
of a non-inferiority, randomized controlled trial
1,2* 3 4 4 5
Tina M Slusher , Bolajoko O Olusanya , Hendrik J Vreman , Ronald J Wong , Ann M Brearley ,
6 4
Yvonne E Vaucher and David K Stevenson

Abstract
Background: Severe neonatal jaundice and its progression to kernicterus is a leading cause of death and disability
among newborns in poorly-resourced countries, particularly in sub-Saharan Africa. The standard treatment for
jaundice using conventional phototherapy (CPT) with electric artificial blue light sources is often hampered by
the lack of (functional) CPT devices due either to financial constraints or erratic electrical power. In an attempt
to make phototherapy (PT) more readily available for the treatment of pathologic jaundice in underserved
tropical regions, we set out to test the hypothesis that filtered sunlight phototherapy (FS-PT), in which potentially
harmful ultraviolet and infrared rays are appropriately screened, will be as efficacious as CPT.
Methods/design: This prospective, non-blinded randomized controlled non-inferiority trial seeks to enroll infants
with elevated total serum/plasma bilirubin (TSB, defined as 3 mg/dl below the level recommended by the American
Academy of Pediatrics for high-risk infants requiring PT) who will be randomly and equally assigned to receive FS-PT or
CPT for a total of 616 days at an inner-city maternity hospital in Lagos, Nigeria. Two FS-PT canopies with pre-tested films
will be used. One canopy with a film that transmits roughly 33% blue light (wavelength range: 400 to 520 nm) will be
used during sunny periods of a day. Another canopy with a film that transmits about 79% blue light will be used
during overcast periods of the day. The infants will be moved from one canopy to the other as needed during the
2
day with the goal of keeping the blue light irradiance level above 8 μW/cm /nm.
Primary outcome: FS-PT will be as efficacious as CPT in reducing the rate of rise in bilirubin levels. Secondary
outcome: The number of infants requiring exchange transfusion under FS-PT will not be more than those under CPT.
Conclusion: This novel study offers the prospect of an effective treatment for infants at risk of severe neonatal
jaundice and avoidable exchange transfusion in poorly-resourced settings without access to (reliable) CPT in the
tropics.
Trial registration: ClinicalTrials.gov Identifier: NCT01434810
Keywords: Filtered sunlight phototherapy, Hyperbilirubinemia, Developing country, Low-cost technologies,
Irradiance, Africa

* Correspondence: tslusher@umn.edu
1
Center for Global Health, Department of Pediatrics, University of Minnesota,
Minneapolis, MN, USA
2
Department of Pediatrics, Hennepin County Medical Center, Minneapolis,
MN, USA
Full list of author information is available at the end of the article

© 2013 Slusher et al.; licensee BioMed Central Ltd. This is an open access article distributed under the terms of the Creative
Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and
reproduction in any medium, provided the original work is properly cited.
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B available, most hospitals an in vitro study [24]. infrared radiation, which,
a lack the resources Using direct sunlight in the absence of sufficient
c necessary to replace for PT has a number of cool- ing, could raise core
k fluorescent lamps, which clinical and practical body temperatures to
g is recommended after drawbacks that could unsafe levels. However,
r 2,000 to make its use undesir- able. several technological
o 3,000 hours of use, and, as Sunlight contains solutions exist for filtering
u a consequence, simply altitude-, seasonal-, and unwanted radiation from
n leave in- effective tubes in time-of- day-dependent any light source, including
d place until they burn out. levels of harmful sun- light, while preserving
Severe neonatal jaundice Moreover, very few ultraviolet A, B, and C the desirable attributes of
(NNJ) or hospitals have appropriate radiation, which can a given energy spectrum
hyperbilirubinemia and irradiance meters for seriously and permanently [25]. When filtered to
its progression to acute meas- uring the intensity damage human skin. It exclude the harm- ful
bilirubin encephalopathy of the blue light emitted also contains significant spectral radiation, the use
(ABE) and kernicterus is by the lamps, resulting in levels of warming of sunlight can be valuable
a leading, yet preventable, few or no devices in environments that have
cause of newborn re- providing the optimal no access to electric lamp
hospitalizations, deaths, level PT.
and disabilities glo- bally of irradiance required The most practical
[1-5]. Phototherapy (PT), for intensive (>30 filters of sunlight are the
which involves exposing a μW/cm2/nm) commer- cially available
newborn’s skin to electric conventional window-tinting films,
lamp-generated blue light, phototherapy (CPT) widely used in vehi- cles
is the standard treatment [21,22]. However, it is not and residential and
for removing excessive uncommon, especially in commercial structures in
bilirubin, ex- cept in areas without access to sunny climates. Although
extreme cases when CPT, for the window-tinting films are
exchange transfusion parents/guardians of traditionally affixed to a
becomes necessary [6]. jaundiced infants to glass surface, these films
Numerous studies from place their babies in can also be stretched over
poorly-resourced direct sunlight unaware a support frame, under
countries suggest that of the potential harm or which an infant basket
severe NNJ represents safety risks. (Figure 1A), bassinet, or
perhaps the largest The scientific potential crib (Figure 1B) can be
unrecognized cause of of sunlight as a possible placed. Our preliminary
neonatal morbidity and treat- ment for NNJ was laboratory bench studies
mortality in the world first demonstrated by in California and field
[4,7]. In sub-Saharan Cremer and colleagues in studies in Nigeria have
Africa, especially in 1958 [23]. His team shown that such films
Nigeria and Kenya, NNJ found that placing naked effectively remove
is a leading cause of infants in sunlight potentially harmful
death in newborn decreased bilirubin levels. radiation, while allowing
nurseries [8-13] and long- This observation led to the transmission of
term neurological the production of the first beneficial blue light re-
impairment in survivors PT device using quired for effective PT.
[14-18]. Unfortunately, PT fluorescent blue light tubes. The levels of irradiance
may not be available in These early studies recorded exceeded that
these countries because of subsequently led to the delivered by the most
the lack of devices and/or development of potent newborn PT
of reliable electrical commercially available, devices. In one of the
power [19,20]. In these easily controlled, field tests in a rural
areas, modern PT devices electricity-requiring hospital in Nigeria, seven
are not readily affordable, artificial blue light sources jaundiced infants were
often break down because for effective, on-demand placed under port- able
of electrical power surges, PT of new- borns in individual or group
and are difficult to industrialized countries. filtered sunlight PT (FS-
maintain due to the The potential efficacy of PT) using film-covered
unavailability of re- direct sunlight PT canopies placed in direct
placement parts. Even compared with CPT has sunlight in the hospital
where PT devices are also been demonstrated in courtyard (Figure 1B,C).
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Body temperature and use in an inner-city mater-
blue light irradiance were nity hospital in Lagos,
monitored every hour, Nigeria. FS-PT safety was
and the infants were deter- mined through
watched closely for the close monitoring of
development of clinical infant temperature,
dehydration and sunburn.
FS-PT was tolerated well
by both newborns and
their mothers and allowed
for maternal bonding
during treatment. None of
the infants developed
significant hypothermia
(defined as <35.5°C), and
displayed no evidence of
dehydration or sunburn.
Six of the infants had
at least one temperature
epi- sode >38.0°C during
their course of FS-PT,
but none exceeded 39°C,
and all recovered after
being returned indoors.
The average time to
being able to return to
FS-PT was 19.7 minutes,
with only two instances
over
60 minutes. Moreover,
placing infants on a
moistened towel during
high ambient
temperatures (>40°C)
quite readily maintained
body temperatures of
infants in cribs.

Observational study on
the safety and potential
efficacy of filtered
sunlight phototherapy
A recent comprehensive
systematic review of
available
evidence worldwide on
PT found no randomized
con- trolled trials (RCTs)
dealing with either
sunlight or en-
vironmental light [26].
Prior to our proposed RCT
to establish the
effectiveness of FS-PT
compared with CPT in a
larger sample of infants,
we conducted an
observa- tional study to
evaluate safety and
potential efficacy of two
previously tested films for
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Figure 1 Filtered sunlight canopies. A: Experimental filtered sunlight canopy with a baby doll; B: Baby placed under a filtered sunlight canopy
in an open lawn in a primary care setting; C: Mother-infant pairs with health workers under a group filtered sunlight canopy in a hospital setting.
Slusher et al. Trials 2013, 14:446 Page 6 of 10
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hydration status, and skin Bili-Blanket Meter II USA). No infant The secondary goal of
for signs of possible (General Electric, developed sunburn or the study is to
sunburn. Therapy was Fairfield, CT, dehydration, nor met demonstrate that the
deemed safe on a given exclusion criteria. Based proportion of infants who
day if the infant did not on these favorable require exchange
have to be removed from findings with our selected transfusion under FS-PT is
phototherapy due to films (Gila Titanium and no worse than that under
needing physician Air Blue 80 pro- duced by CPT, with a non-
treatment for sunburn or CP Films Inc. Subsidiary inferiority margin of 5%
dehydration, due to of Eastman Chemical Co. based on a clinical
persistent temperature Fieldale, VA, USA), we set rationale that FS-PT is
instability defined as two out under the second non-inferior to CPT and
or more episodes of phase of this project to still better than no treat-
temperatures <35.0 or demonstrate primarily in a ment. This was also
>39.0°C, or due to fail- RCT that FS- PT is just as informed by the results
ure to return to efficacious as CPT in the of a meta- analysis of
normothermia (defined as treatment of infants with RCTs comparing CPT with
35.5 to 38.0°C) within 1 or at risk of severe NNJ. no treatment which
hour of being removed estimated that 10 infants
from FS-PT. Efficacy was needed to be treated with
evaluated by measuring M CPT to prevent an
the rate of rise/decline e exchange transfusion [26].
in total serum/plasma t
bilirubin (TSB) levels. h
Treatment was deemed o
safe and efficacious if the d
infant was able to stay in s
the FS-PT canopy for ≥5 /
hours per day and the rate d
of rise of TSB was <0.2 e
mg/dl/hour for infants s
≤72 hours of age or if TSB i
decreased for infants >72 g
hours of age. This study n
was concluded in August A
i
2012, details of which are m
scheduled for publication s
shortly. In summary, 203
term and near-term a
newborns (≤14 days old) n
with clinically sig- nificant d
jaundice as assessed by
TSB levels were enrolled. h
They received treatment y
under a FS-PT canopy p
o
over a period of 227 days.
t
Hourly measurements of h
axillary body temperatures e
and monitoring of s
sunburn, dehydration, and e
irradiances of FS-PT s
were performed. The The primary goal of this
results showed that FS- study is to demonstrate
PT was efficacious in that the efficacy of FS-PT
94% (164/175) of the is no worse than that of
infants studied. Average CPT, with a non-
irradiance from FS-PT inferiority margin of 10%.
was In effect, our null hypoth-
37 ± 14 (range 8 to 65) esis is that this margin is
μW/cm2/nm as measured above 10% suggesting that
by the FS- PT is inferior to CPT.
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S infants (15%) would be with elevated TSB,
t expected to qualify for defined as C
u PT. It is pos- sible at 3 mg/dl below the level P
d recommended by the T
this location to give
y American Academy of .
routine care, IV fluids,
antibiotics, oxygen, and Pediatrics (AAP) [27] for
d PT in high-risk infants,
e medications without
inter- rupting PT. The will be considered at high
s
i average maximum risk. The high-risk
g temperature in Lagos is classification category of
n 32°C (90°F) during the the AAP guideline was
This is a prospective, non- dry season (November to selected because
blinded, single center, March), with a maximum laboratory evaluation for
ran- domized two-stage recorded temperature of hemolysis will not be
controlled non- 40°C (104°F), making FS- consistently available
inferiority clinical trial. PT possible even with during the study, and
During the first stage of infants unclothed or Nigerian in- fants are
the study, infants will be minimally clothed. In the known to be at higher
referred from elevated rainy season it should be risk for severe NNJ sec-
transcutaneous bilirubin possible to maintain ondary to glucose-6-
(TcB) screening and satisfactory irradiances in phosphate dehydrogenase
enrolled for the definitive the absence of an (G6PD) deficiency [28].
TSB estimation. Only excessively overcast sky. This TSB level was chosen
infants with significantly This site was chosen for also because many
elevated TSB levels will the maiden study to hospitals begin PT about
qualify for inclusion into ensure that back- up 2 to 3 mg/dl below the
the second stage of the neonatal care services are current level in the
study for PT treatment readily available when United States, due to the
and will be randomly required until we have severity of NNJ and the
assigned to re- ceive FS- the required safety and sub-optimal PT treatment
PT or CPT. efficacy data. in most locations in
Nigeria.
S D
t e P
u f r
d i i
y n m
i a
s t r
e i y
t o
t n o
i u
n o t
g f c
The study location is h o
Island Maternity Hospital i m
(IMH), Lagos, Nigeria, g e
which is a state-owned h The primary outcome for
- the RCT is efficacy of
hospital. It has a special
r FS-PT
care baby unit with CPT i c
and other basic neonatal s o
care facilities, including k
m
intravenous (IV) fluids, p
antibiotics, and exchange t a
transfusion. Ventilator h r
sup- port and pumps r e
for giving IV fluids are e d
s
not avail- able. It is a h
180-bed residency o w
teaching hospital with l i
about 300 deliveries per d t
month of which 45 All jaundiced infants h
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the propor- tion of safe The minimum sample
v days where a given therapy size was estimated using
a was used in which the the fol- lowing
l
therapy was efficacious, assumptions: 1) the
u
a will be compared. FS-PT average efficacy of CPT
t will be considered at least is
i as efficacious as CPT if the 80%; 2) the average
o average efficacy on days efficacy of FS-PT is 80%;
n where FS-PT was used is 3) there will be the same
no worse than number of infants
c 10% less than the average assigned to both groups;
r efficacy on days where 4) the delta value is 10%
i CPT
t
- that is, we want to
w demonstrate that FS-PT
e
r a is no more than 10%
i s worse than CPT; and 5)
a 80% power, one-sided
Change in TSB level per u alpha = 0.025.
hour of therapy defined s Under these
as a binary variable. The e
assumptions, a total of
TSB level will be measured d
504 days, or 252 days in
.
immedi- ately before each treatment group,
beginning therapy on a will be required. This cal-
S
given day and imme- culation gives the
e
diately after therapy is c required number of
completed that day, and o treatment days that are
the change in bilirubin n evaluable for efficacy.
level in mg/dl per hour d Since efficacy will be eval-
of therapy will be a uated only for days in
calculated. For infants r
y
which the treatment was
who are less than 72 deemed safe, the sample
hours old in the morning, size was increased to
o
the treatment will be u account for the possibility
judged effica- cious if the t that the proportion of
bilirubin level rises more c safe days might be as low
slowly than 0.2 mg/dl per o as 90%. Assuming that the
hour of therapy that day. m safety of both FS-PT and
For infants who are more e
CPT is 90%, a sample
than 72 hours old, the A secondary outcome for size of 560 total days is
treatment will be judged this trial is the required. Assuming that a
efficacious if the bilirubin proportion of enrolled typical course of
level falls. Efficacy will be infants who require treatment lasts 1 day, both
evaluated only for days in exchange transfusion. FS- for FS-PT and CPT, then
which the treatment was PT will be considered at 560 infants, or 280 infants
deemed safe (that is, when least as efficacious as CPT
the infant did not have to if the pro- portion of
be removed from PT due infants who require
to a need for physician exchange transfusion
treatment for sunburn or under FS-PT is no more
de- hydration, persistent than 5% greater than the
temperature instability proportion under CPT.
defined as two or more
episodes of temperatures S
a
<35.0 or >39.0°C, or
m
failure to return to p
normothermia (defined as l
35.5 to e
38.0°C) within 1 hour of
being removed from PT). s
The average efficacy of i
each type of PT, defined as z
e
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in each group, will be required. Anticipating up to 10%
loss due to rainy days (in the FS-PT group), delisting of
infants by parents or guardians, or missing data (in both
groups), we will enroll 616 infants, or 308 infants in each
group. From our year 1 data in the preceding observa-
tional study only 66% of the 826 infants referred for ele-
vated TcB had significant elevated TSB levels, hence 915
infants or more will be enrolled for stage 1 bilirubin esti-
mation until the total requirement of 560 treatment days
is reached (Figure 2).
Subject recruitment
Infants born in the hospital will be screened daily from 0
to 14 days of life for elevated TSB using TcB measure-
ments, while in the hospital or, if discharged before 14
days, in the community by nurses sent out from the hos-
pital when possible. Infants from the community will
also be screened if within 14 days they choose to come
to the study site for screening. The parents will be asked
to return with their infants to the hospital if the parent
observes new-onset jaundice between 1 and 14 days of
life. If the TcB is not elevated during the first 14 days of
life, the subject will cease to be eligible for the study. If
the TcB is elevated and the other study inclusion and ex-
clusion criteria are met, then the infant will be recruited
for the study after informed consent in writing or thumb
printing is obtained from a parent or guardian. The in-
fant will then have a TSB measured. Enrolled infants
with elevated TSB (defined as 3 mg/dl below the level
recommended by the AAP [27] to begin PT in high-risk
infants) will be randomly assigned to receive FS-PT or
CPT. Enrolled infants with TSB levels that are not
elevated as defined above will not be treated with PT.
They will continue to be screened for elevated TcB as
described
Raised TcB value
TSB estimation
Raised TSB
CPT
Figure 2 Enrolment flow chart. CPT, conventional phototherapy; FS-PT, filtered sunlight phototherapy; TcB, transcutaneous bilirubin; TSB, total
serum/plasma bilirubin.
Page 11 of 10
above. If their subsequent TcB levels are not elevated
dur- ing the first 14 days of life, the infant will be
withdrawn from the study.
Subject screening
Screening criteria prior to enrolment are shown in
Table 1.
Prior and concomitant therapy
All infants who meet the AAP guideline for the initiation
of PT will be treated with CPT at night or when it is not
possible to use FS-PT, secondary to rain or overcast sky.
CPT will be performed per hospital standards. Addition-
ally, since the study physicians only serve as consultants
for patients requiring treatment for NNJ, patient man-
agement decisions, including the need for and timing
of exchange transfusion, administration of antibiotics or
other testing, will be at the discretion of the attending
physician. AAP guidelines will be used to direct the deci-
sion of when to perform exchange transfusion, but the
final decision will be that of the attending physician.
Generally, exchange transfusion is performed in any
term infant in Nigeria whose TSB level is ≥20 mg/dl or
in any infant with neurologic signs of ABE, regardless of
the recommendations in the AAP guideline.
Inclusion criteria
Subjects will be eligible to participate in the study if all
of the following conditions exist:1) at time of birth,
infant is ≥35 weeks gestation (or >2.2 kg if gestational
age is not available); 2) infant is ≤14 days old at the time
of enrollment; 3) at time of enrollment, infant has an ele-
vated TcB defined as 3 mg/dl below the level recom-
mended for high-risk infants per AAP guideline or
higher;
Screening
All infants receive
TcB
TcB within
acceptable limits
Excluded but
TSB within
continue with daily
acceptable limits
TcB
FS-PT
Table 1 Screening criteria prior to enrolment
Test Screening requirement
Gestational age and/or weight Greater than or equal to 35 weeks gestation (or >2.2 kg if gestational age is not available).
Infant must be ≤14 days old at the time of first PT.
TcB Screened daily for the first 7 days of life if in hospital and, when possible, in the community
if discharged before 7 days of life or if the patient chooses to come in for screening up
to14 days of life. If the TcB is elevated (elevated will be defined as a point 3 mg/dl below
that recommended by the AAP for PT in high risk infants and above) at any time during
the first 14 days of life, a TSB will be done.
Physical examination (dehydration, oxygen use,
ABE, life expectancy, sunburn)
AAP, American Academy of Pediatrics; ABE, acute bilirubin encephalopathy; PT, phototherapy; TcB, transcutaneous bilirubin; TSB, total serum/plasma bilirubin.
4) parent or guardian has given consent for the infant to
participate.
Exclusion criteria
Subjects will be excluded from participation in the study
if any of the following conditions exist at the time of en-
rollment:1) infants with a condition requiring referral for
treatment not available at the hospital study site and/or
CPT unit; 2) infants with a life-expectancy of <24
hours;
3) infants requiring oxygen therapy; 4) infants clinically
dehydrated or sunburned; 5) infants with a temper-
ature <35.5°C or >38°C; 6) infants with ABE on clinical
examination; 7) infants meeting the criteria for exchange
transfusion.
Inclusion and exclusion criteria are only applicable at
the time of enrollment before randomization to prevent
bias of the treatment comparison.
Exit/discontinuation/withdrawal criteria
Subjects will exit the study (will cease to receive FS-PT
or CPT) if any of the following conditions occur: 1) per-
sistent temperature instability defined as two or more
episodes of temperatures <35.0°C or >39.0°C; 2) failure
to return to normothermia (defined as 35.5°C to 38.0°C)
within 1 hour of being removed from PT; 3) physician
treatment for dehydration or sunburn is required; 4) TSB
level reaches exchange transfusion levels; 5) inter-current
illness not compatible with PT or needing more care
than can be provided in the FS-PT canopy or CPT ward;
6) infants requiring transfer to another hospital; 7) parent
request; 8) subject death; 9) subject completes the proto-
col (TcB or TSB level is no longer elevated); 10) subject’s
well-being, in the opinion of the Investigator, would be
compromised by study continuation; 11) Institutional
Review Board (IRB) recommendation; or 12) subject’s
risk level indicates PT should be stopped.
Infants who have been withdrawn from the study will
have a physical examination and a final TcB. Safety data
will be analyzed for all days in which the subjects spend
any time under either FS-PT or CPT.
Subjects cannot be dehydrated, sunburned, using oxygen, or have ABE or a life expectancy
<24 hours at the time of examination by the physician for enrollment in the treatment
phase of the protocol.
Efficacy will be evaluated for all days in which the
treatment was deemed safe (that is, when the infant did
not have to be removed from PT due to a need for phys-
ician treatment for sunburn or dehydration, due to per-
sistent temperature instability defined as two or more
episodes of temperatures <35.0 or >39.0°C, or due to
failure to return to normothermia (defined as 35.5 to
38.0°C) within 1 hour of being removed from PT).
Randomization scheme
Enrolled infants with elevated TSB (defined as 3 mg/dl
below the level recommended by the AAP to begin PT in
high-risk infants) will be randomly assigned to receive FS-
PT or CPT. A block randomization procedure with vari-
able block sizes will be used to maximize unpredictability.
The randomization assignments of FS-PT or CPT will be
printed on sequentially numbered sheets of paper and
enclosed in opaque, sealed, sequentially numbered enve-
lopes. The sealed envelopes will be prepared indepen-
dently by the study statistician based in the USA and
transported to Nigeria by the regulatory sponsor. When
an enrolled infant’s TSB level is obtained and found to be
3 mg/dl or more below the AAP threshold for high-risk
infants the study nurse will request the next envelope.
The envelope will be opened and both the envelope num-
ber and the treatment assignment will be recorded on the
case report form. The laboratory technician responsible
for measuring the serum bilirubin level will be unaware of
the sequence of treatment allocation of either FS-PT or
CPT for each eligible infant and will not be involved in ad-
ministering PT. The study will not be blinded as it is not
physically possible to blind either the participating infants
or parents, nor the hospital personnel.
Laboratory testing procedures
Glucose-6-phosphate dehydrogenase
Because of the high prevalence of G6PD deficiency in our
study population, enrolled infants will be routinely
screened for this condition using simple and inexpensive
supplies. The method will be based on the fluorescent
blood spot originally i life for elevated TcB while to participate, consent will
developed by Beutler and m in the hospital or, if be documented on the
colleagues [29]. This test e discharged before 14 days, consent form in writing or
n in the community by thumb printing.
has been considered a
standard method of G6PD nurses sent out from the
c hospital when possible. P
screening especially in
o r
resource-poor settings, Infants ≤14 days old from
l e
since inexpensive l the community presenting
to the study site will also -
reagents and materials e t
can be used. c be screened. The parents r
t will be asked to return e
B i with their infant to the a
i o hospital if the parent t
l n m
observes new on- set
i Blood specimens for e
jaundice between 1 and 14
r TSB measurements will n
days of life.
u generally be collected by t
b heel-stick. Specimens for
i S
G6PD, blood type and Rh (
n c
will be drawn by s
r
TSB will be estimated t
venipuncture. e
using standard methods. a
e
Hematocrit testing will be g
C n
done using standard e
l i
laboratory methods. i n
g 1
n
During the screening )
C i
o c period, information about The enrolled infant will
o a the baby and the mother then have a TSB drawn
m l will be collected. TcB (stage 1) using the
b testing will be done for Advanced Bilirubinometer
s p Stat-Analyzer, Model BR2
t
up to 14 days, using
r (Advanced Instruments,
e Minolta AirShields
o Inc, Norwood, MA,
s c Jaundice Meter JM-103
t (Draeger Medical USA) before treatment
e
i d Systems, Inc., Telford, PA, (stage 2). Enrolled infants
n u USA) either in the with elevated TSB qualify
g r for inclusion into the
hospital or in the com-
e munity. If the TcB is not second stage of the
a s
elevated during the first
n C
d r
14 days of life, the subject
i will not be eligible for the
b t study. If at any time
l e during screening the
o r infant’s TcB level rises to
o i within 3 mg/dl below the
d a
AAP threshold [27] for
high- risk infants,
t f
inclusion/exclusion criteria
y o
r will be reviewed. If the
p
infant is eligible, the
i
n a infant will be recruited
g d for the study. The
Coombs testing and m infant’s mother and/or
blood typing will be i father will be approached
performed in the blood s to ask if they are
s interested in participating
bank laboratory at IMH. i
in the research study. If
o
S n they are willing, the
p Infants born in the consent form for the study
e hospital will be screened will be discussed. If
c informed consent is given
daily from 0 to 14 days of
study and will be randomly 2
below 8 μW/cm /nm or μW/cm2/nm. The
assigned to receive FS-PT at any point during the irradiance will be
or CPT. Enrolled infants day during a rainy/cloudy measured at an infant’s
with TSB levels that are day when the irradiance abdomen level with a
not elevated as defined stays below 8 Bili- Blanket Meter II
2
above will not proceed to μW/cm /nm. If the every half hour in infants
the second stage to be irradiance persists below under FS-PT (if possible,
2
treated with PT. 8 μW/cm /nm for more additional measurements
However, they will than 1 hour and the in- may be done) and daily in
continue to be screened fant qualifies for PT per those infants under CPT.
for elevated TcB as the AAP guideline, CPT The proportion of blue
described above. If their will be initiated. If the light accessible to the
sub- sequent TcB levels irradiance again exceeds subjects under FS-PT
2
are not elevated during the 8 μW/cm /nm then the canopies is dependent on
first 14 days of life, the infant may again be placed the location of treatment
infant will be withdrawn in FS-PT. canopies in relation to
from the study. All in- surrounding buildings. It
T is therefore imperative
fants who meet the AAP
r
guideline for the initiation that the treatment
e
of PT will be treated with a canopies be placed in a
CPT at night or when it is t location with proven day-
not possible to use FS-PT, m long sun exposure
secondary to rain or e throughout the year,
excessive cloud cover n preferably one also
t protected from potentially
(defined as cloud cover
persisting for more than 2 violent wind currents and
c surface dust gener- ated
hours). FS-PT will be
a
optimized in all infants by n
by traffic. In fact, the
using white cloth lining the o single most important
bottom and sides of the cot p reason for replacing films
and exposing the in- fant i is wind damage. A roof
maximally. CPT will be e top terrace,
performed per s
international standards of Two FS-PT canopies will
be used: one fitted with
practice [27].
the
Gila Titanium film and the
T
other fitted with the Air
r
e
Blue
a 80 film because of
t concerns about irradiance
m and heat. The Titanium
e canopy transmits
n approximately 33% blue
t
light in the wavelength
range 400 to 520 nm with
(
much lower heat and will
s
t be used during sunny
a periods of the day. The
g Air Blue canopy
e transmits roughly 79%
blue light as well as heat
2 and will be used during
) cooler over- cast periods
FS-PT will be started in of the day. The infants
the morning after the will be moved from one
irradiance level inside the canopy to the other as
canopy is at least 8
2 needed during the day,
μW/cm /nm, and will be when the weather changes,
stopped in the late with the goal of keeping
afternoon when the
the irradi-
irradiance level drops
ance level above 8
presently in use in our h observational study in below 35°C or exceed
study, has proven to be a o which infants were 39°C on two occasions
very satis- factory location. u monitored closely, no will be ex- cluded from the
A courtyard of adequate r untoward effects of study.
size surrounded by low s temperatures within the
buildings could be even chosen range were re- D
more suitable. Finally, per- i ported. If the axillary e
haps most ideal and n body temperature falls h
practical, will be the below y
F 35.5°C the infant will be d
construction of a suitable r
FS-PT room or a small S placed skin-to-skin with
- a
permanent building with the mother and/or t
P brought inside until the
a glass or plexiglass roof, T
i
in an appropriately temperature returns to o
/
“sunny” part of a hospital. the normal range of n
C
This would be a most 35.5 to 38.0°C. If the The nurse will also
P
ideal solution to pre- vent T axillary body temperature check hourly for clinical
issues with wind, dust, . goes above 38.0°C, the signs of dehydration in
security, and so forth. infant will be brought the form of dry mucus
How- ever, such a T indoors and/or placed in membranes, sunken eyes,
treatment facility may e the shade and/ or placed dry eyes, and skin
overtax local resources. m on a wet towel until the tenting. The physician
p body temperature returns may elect to increase
e to normal at which time the mother’s
T r
r FS-PT will resume. The breastfeeding fre- quency
a
e t time it takes to return to while continuing with
a u normal will be recorded. the FS-PT if the diag-
t r Infants who do not return nosis is mild
m e dehydration. Whenever
e
to normothermia within
n 1 hour will be taken out the diagnosis of moderate
t m of FS-PT for that day. If or severe dehydration is
e the axillary body made, the infant will be
a withdrawn from the
d temperature falls below
s
u 35°C the infant will be study for treatment. Be-
u
r r placed skin-to-skin with cause both nutrition and
a e the mother or wrapped hydration are important
t m in the prevention and
well and brought inside
i e until the temperature treatment of severe
o n
n returns to normal. If the NNJ, infants will be
t allowed and encouraged
Generally, the infants will axillary body temperature
s
be placed under FS- goes above 39.0°C, the to breastfeed ad lib and
Infant temperature will be
PT/CPT infant will be brought often. The FS-PT canopy
measured hourly while
from 9:00 am to 5:00 pm indoors and placed on a allows for the mother to
under FS-PT and CPT
(target minimum wet towel until the body stay with the infant and
and monitored based on
duration of temperature returns to to feed as often as she
World Health
5 hours per day for any normal at which time FS- de- sires. Mothers will be
Organization guidelines
infant in the study at PT will resume. The time comfortably seated on
for normothermia,
10:00 am, or 65% of total it takes to return to custom- made reclined
hypothermia, and
time between start time normal will be recorded. chairs (painted white) and
hyperthermia [30]. For the
and 5:00 pm for infants Infants who do not provided with white
purpose of this study the
enrolled after 10:00 am). return to normothermia aprons for breast-feeding
normal temperature
The infants’ eyes will be within 1 hour will be or when they need to
range of 36.5 to 37.5°C
protected with low-cost taken out of FS-PT for carry their babies (Figure
[30] was modified slightly
eye covers made from the that day. Infants whose 1C). If the mother has
to 35.5 to 38.0°C in
elastic tops of any color axillary body temperature chosen to use artificial
consultation with a
socks. Bilirubin kinetics fall feeds, those will also be
neonatologist to provide a
will only be calculated allowed and en- couraged
broader but safe
for infants who are able ad lib. For CPT, the
temperature limit for term
to spend at least mother will be allowed
and near-term infants. In
5 and encouraged to take
addition, during the prior
the infant out as needed
safety and efficacy
for bathing or feeding. Efficacy will be tested by
measuring TSB levels
S prior to the placement of
u the infant under PT each
n morning to establish
b baseline TSB levels.
u
r Infants with morning TSB
n levels that meet the
The nurse will assess for criteria for PT will be
sunburn by looking for randomized for FS-PT.
the onset of pink skin Repeat TSB levels will be
every hour. Most infants obtained at the end of
are born relatively light each day spent under
skinned and darken over FS-PT and between
time. Infants born very ~4:00 to
dark and for whom it 5:00 pm for infants under
would be difficult to CPT to estimate the
recognize pink skin are effective- ness of the
also much less likely to treatment for the day and
become sunburned. to determine if the
Absence of sunburn requirement for night-
determined in consult- time PT is met.
ation with a
dermatologist is defined
as the absence of new-
onset pink skin. If the
infant has the onset of
pink skin, the attending
physician will be notified
and will verify the finding.
If the physician makes the
diagnosis of sunburn, the
infant will be immediately
withdrawn from the study.
Mothers will be allowed
and encouraged as much
as possible to stay with
their babies, but will be
able to leave as needed
to care for themselves or
other needs. Study nurses
will care for the infants
during their mother’s
absence.

T
r
e
a
t
m
e
n
t

e
f
f
i
c
a
c
y
D appro- priate methods, assessment of the number 2) an assessment of the
a such as Pearson’s chi- and type of serious casual relationship between
t square test for cat- adverse events. The the ad- verse effect and the
a clinical course of each
egorical variables and investigational device or, if
two-sample t-tests for event will be followed applicable, the other study
c until resolution,
continuous variables. The treatment or diagnostic
o stabilization, or until it
l primary objective is to product(s).
l compare the effi- cacy of has been determined that
e FS-PT and CPT. A 95% study treatment or Ethical considerations
c exact binomial confi- participation is not the This study was approved
t dence interval for the true cause. by the IRBs/Ethical
i difference in efficacy All observed or Commit- tees at the
o volunteered adverse effects
between the FS-PT treated University of Minnesota,
n
and CPT control groups and abnor- mal test Minnesota Medical
will be calcu- lated. FS-PT findings, regardless of Research Foundation
a
will be deemed non- treatment group, if applic- (Hennepin County
n
d inferior to CPT if the able, or suspected causal Medical Center), and the
calculated confidence relationship to the Lagos State Government.
a interval does not extend investigational device or, if This study is being
n more than 10% below the applicable, other study conducted according to
a equivalence point. treatment or diagnostic United States and
l We plan to conduct product(s) will be international standards of
y recorded in the subjects’
three distinct analyses: an Good Clinical Practice (21
s case histories. For all
i intent- to-treat analysis CFR 812 and Inter-
based on the assigned adverse effects, sufficient national Conference on
s
treatment for each information will be pur- Harmonization guidelines),
Data will be collected on
enrolled infant, an as- sued and/or obtained so as applic- able government
paper case report forms
treated analysis based on to permit: 1) an adequate regulations and
and entered via a web
the actual treatment deter- mination of the Institutional research
interface into a secure
received on a given day outcome of the effect (that policies and procedures.
database. The study data
and a per- protocol is, whether the effect The parents/guardians of
will be collected and
analysis including only should be classified as a poten- tial subjects for this
managed using REDCap
enrolled infants who serious adverse effect); and study will be provided a
(Research Electronic Data
Capture) electronic data received the assigned consent form describing
capture tools hosted at treatment on all of their this study and providing
the University of treat- ment days. sufficient information for
Minnesota’s Academic the parents/guardians to
Health Center. REDCap is Safety make an informed
a secure, web-based monit decision about their child’s
oring participation in this study.
application designed to and
support data capture for The consent form has
advers
research studies, pro- e been submitted with the
viding: 1) an intuitive events protocol for review and
interface for validated The Principal Investigator approval by the relevant
data entry; will oversee the safety of IRBs/Ethical Committees
2) audit trails for tracking the study, including careful for the study. The formal
data manipulation and assessment and consent of a
export procedures; 3) appropriate reporting of parent/guardian, using the
automated export adverse events to IRB-approved consent
procedures for seamless relevant authorities at form, will be obtained
data downloads to IMH. All anticipated before the infant is
common statistical adverse events such as subjected to any study
packages; and sunburn, dehydration, and procedure. This consent
4) procedures for temperature instability as form will be signed or
importing data from well as un- anticipated thumb-printed by the
external sources. adverse events occurring parent/guardian, and the
Demographic data will during the study period investigator-designated re-
be summarized and will be recorded and search professional
compared closely monitored. obtaining the consent. A
between the treatment Medical monitoring will blank copy of the IRB-
and control groups using include a regular approved form will be
kept on-site and by the
sponsor-investigator.

Trial status
The first participant was
randomized on 29
November
2012 and recruitment is
ongoing as of 31 July 2013.
Abbreviations
AAP: American Academy of
Pediatrics; ABE: Acute bilirubin
encephalopathy; CPT:
Conventional phototherapy; FS-
PT: Filtered sunlight
phototherapy; G6PD: Glucose-6-
phosphate dehydrogenase; IMH:
Island Maternity Hospital; IRB:
Institutional Review Board; IV:
Intravenous; NNJ: Neonatal
jaundice;
PT: Phototherapy; RCT:
Randomized controlled trial;
REDCap: Research Electronic
Data Capture; TcB:
Transcutaneous bilirubin; TSB:
Total serum/ plasma bilirubin.

Competing interests
The authors declare that they have
no competing interests.

Authors’ contributions
TMS, BOO, HJV, RJW, AMB, YEV
and DKS contributed
substantially to the conception,
design and implementation of
this trial. BOO and TMS drafted
the manuscript. TMS, BOO, HJV,
RJW, AMB, YEV and DKS
reviewed the manuscript
critically for intellectual content.
All authors read and approved
the final version before
submission.

Acknowledgements
The authors are grateful to all
participating mothers in this study
as well as the management and
staff of IMH for their support. We
acknowledge the exceptional
support from Lekan Kehinde and
other full-time research staff during
the pre-trial studies. We thank Vinod
K Bhutani, Professor of Pediatrics at
Stanford University, for his
contribution to the analysis of
efficacy of the
FS-PT and consultation regarding the
study. We thank Richard P Wennberg
for his help in accomplishing a
reasonable temperature limit
for full and near-term infants
and Martha S Housholder for
her help in handling early
dermatological features of sunburn
in newborns. Thrasher Research
Fund for providing the grant that
makes this research possible.
Clinical and Translational Science
Institute Grant support
(UL1TR000114 from the National
Center for Research Resources).
Author details
1
Center for Global Health,
Department of Pediatrics,
University of Minnesota,
Minneapolis, MN, USA.
2
Department of Pediatrics,
Hennepin County Medical Center,
3
Minneapolis, MN, USA. Center for
Healthy Start Initiative, Dolphin
Estate, Ikoyi, Lagos, Nigeria.
4
Neonatal and Developmental
Medicine
Laboratory, Division of
Neonatology, Department of
Pediatrics, Stanford University
Medical Center, Stanford, CA,
5
USA. Biostatistical Design and
Analysis Center, Clinical and
Translational Science Institute,
University of Minnesota
Academic Health Center,
6
Minneapolis, MN, USA. Division
of Neonatal/Perinatal Medicine,
School of Medicine, University of
California at San Diego, San
Diego, CA, USA.
Received: 6 August 2013
Accepted: 16 December 2013
Published: 28 December 2013
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